ABSTRACT An estimated 13 million preterm births (PTBs) occur annually worldwide, and PTB is the single most significant contributing factor to neonatal morbidity and mortality. Mechanisms underlying preterm birth are unknown hampering development of effective prediction and prevention strategies. PTB is linked to local and distant infections and recent data suggests that vaginal bacterial microbiome early in pregnancy is associated with subsequent preterm birth. Viral infections behave differently during pregnancy, with common viral infections such as varicella and influenza causing much more severe disease during pregnancy and human papillomavirus, the causative virus in cervical cancer, associated with a 2-fold increased risk for PTB. However, comprehensive assessment of vaginal viral communities during pregnancy has not been performed. Lastly, although maternal inflammation is one of the leading triggers for PTB the precise constellation of inflammatory signals is not known. We propose that examining microbial communities or host response alone is incomplete, but that their combination will lead to refined definitions of appropriate and inappropriate microbe-maternal biology and shed new light on the old problem of PTB. Our central hypothesis is that preterm birth can be estimated by a combination of three criteria: vaginal bacterial communities, vaginal eukaryotic viral communities, and maternal inflammatory response. We have an interdisciplinary team assembled including perinatologists, epidemiologists, virologists, and genomics informatics experts, leveraging the unique capabilities of the McDonnell Genome Institute at Washington University in St. Louis, a well-established pregnancy bio-specimen and clinical data infrastructure, and a high-PTB burdened racially diverse patient population to test this novel hypothesis. The aims of this project are: 1) Determine the ability of bacterial and viral communities in the vagina and their dynamics over time to predict preterm birth 2) Determine the ability of the host inflammatory response in the vagina in the context of microbial communities to predict preterm birth. The proposed research is innovative, for the first time, comprehensively characterizing the eukaryotic vaginal virome simultaneously with vaginal bacterial communities and longitudinally capturing the maternal response to these communities. We employ an efficient study design, a well-established research infrastructure, and renowned genome sequencing expertise to test a physiologically plausible but uninvestigated paradigm that bacterial and viral communities in concert with the maternal host response can predict PTB.